The dentate gyrus of the hippocampus is unusual because it continues to produce new neurons in adulthood in a variety of mammals, ranging from rodents to primates. Exposure to learning tasks that require the hippocampus for acquisition enhances the survival of adult-generated neurons in the dentate gyrus. In addition, adult female rats produce more new neurons than males, and these sex differences are positively correlated with sex differences in hippocampal-dependent learning. These findings indicate that learning influences the survival of new hippocampal neurons and raise the possibility that adult-generated granule neurons are involved in hippocampal-dependent learning. The broad, long-term objectives of this proposal are to characterize the influence of ovarian steroids and learning on the production, survival and gene expression of hippocampal granule neurons generated in adulthood in both sexes. Moreover, the potential role that new granule neurons play in hippocampal-dependent learning and memory will be explored. Using associative learning paradigms of trace classical eyeblink conditioning and the Morris spatial water maze, the role of hormones and experience in the production and survival of new granule neurons in males and females will be investigated with markers of proliferating cells, such as 3H-thymidine and bromodeoxyuridine, combined with immunocytochemistry for neuronal and glial markers. Combined in situ hybridization and immunocytochemistry will be used to explore changes in expression of genes important for cell survival, synaptic plasticity and/or learning, such as NMDA receptor subunits, BDNF and bcl-2, specifically in adult-generated granule neurons following associative learning. Furthermore, the function of hippocampal granule neurons generated in adulthood will be explored in animals depleted of new neurons by endocrine manipulations or treatment with selective toxins for proliferating neuronal precursors and then tested on tasks that require the hippocampal region for acquisition. This proposal is relevant to disorders or age- and disease-related cognitive decline which can be ameliorated by ovarian steroids. In addition, these studies may provide insight into mechanisms of neuronal regeneration.